Glaucoma is a leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is a strong risk factor and remains the only modifiable target for intervention. However, the mechanisms causing elevated IOP remain poorly understood. Using Oculocerebrorenal syndrome of Lowe, a rare X-linked disease that presents with congenital glaucoma, we have found evidence that OCRL is an important regulator of trafficking in the eye that controls IOP. OCRL is an inositol phosphatase mutated in Lowe syndrome. OCRL localizes within the primary cilium, a subcellular organelle that plays a mechanosensory role in fluid flow. We have identified patients with Lowe syndrome who are born with congenital glaucoma and have characterized their mutations. We discovered that OCRL interacts with TRPV4, a mechanosensory channel in the primary cilia and that modulation of TRPV4 affects IOP in mice. Thus we hypothesize that OCRL plays a critical role in the recruitment of TRPV4 to the cilia in the trabecular meshwork to regulate aqueous outflow.
Our aims are to (1) determine the mechanism of OCRL transport in the primary cilium in the trabecular meshwork, (2) determine the functional role of OCRL and TRPV4 interaction in the primary cilium, (3) determine whether targeting TRPV4 can reduce IOP in murine models. The experiments of this proposal may facilitate the discovery of new glaucoma therapies that can reduce the burden of blindness.

Public Health Relevance

Lowering eye pressure is the only treatment for glaucoma, a leading cause of irreversible blindness in the world. Using cell biology, animal models, and human patient cells, we will examine the signaling pathway of primary cilia within trabecular meshwork as a natural sensor for eye pressure. Novel methods targeting this 'pressure sensor' will be used to lower intraocular pressure and a potential treatment for glaucoma patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY025295-04
Application #
9669035
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2017-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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